Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells - A novel mechanism for maintenance of intestinal inflammation.
Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells - A novel mechanism for maintenance of intestinal inflammation.
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人肠道肌成纤维细胞沉积的 VI 型胶原蛋白增强了 T 细胞的粘附性——这是维持肠道炎症的一种新机制。
DOI：
10.1016/j.matbio.2022.09.001
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Le,HongngaT
中科院分区：
文献类型：
--
作者：
Lin,Si-Nan;Musso,Alessandro;Wang,Jie;Mukherjee,PranabK;West,GailA;Mao,Ren;Lyu,Ruishen;Li,Jiannan;Zhao,Shuai;Elias,Michael;Haberman,Yael;Denson,LeeA;Kugathasan,Subra;Chen,Min-Hu;Czarnecki,Doug;Dejanovic,Dina;Le,HongngaT
目的：炎症性肠病（IBD）引起慢性肠道损伤和细胞外基质（ECM）重塑。ECM可通过调节免疫细胞功能（包括细胞粘附）在炎症中发挥积极作用，但该假设尚未在IBD.Design中进行测试：测试来自IBD和对照的原代人肠肌成纤维细胞（HIMF）衍生的ECM、3D脱细胞结肠或ECM分子涂覆的支架的T细胞粘附性。通过蛋白质组学分析基质体。使用功能性整合素阻断剂来研究潜在的机制。分析的小儿克罗恩病（CD）风险的起始队列被用来探索改变ECM基因表达作为一个潜在的预测未来复杂的疾病course.Results：HIMF衍生的ECM和3D脱细胞结肠ECM IBD结合更多的T细胞相比，控制。对照组HIMFs暴露于促炎细胞因子IL-1 β和肿瘤坏死因子（TNF）后，细胞外基质对T细胞的粘附能力增加，而转化生长因子β1（TGF-β1）则降低。HIMF衍生的ECM的基质体分析揭示胶原VI是T细胞粘附差异的主要原因。HIMF中的VI型胶原蛋白敲除降低了粘附T细胞，正如整合素αvβ1的阻断一样。儿童CD患者活检组织中VI型胶原基因表达升高与未来狭窄性疾病的风险有关。结论：IBD中HIMF衍生的ECM结合了数量显著增加的T细胞，这依赖于VI型胶原和整合素αvβ1。VI型胶原表达是未来复杂CD病程的危险因素。阻断免疫细胞滞留可能代表了治疗IBD的一种新方法。
Objective:Inflammatory bowel diseases (IBD) cause chronic intestinal damage and extracellular matrix (ECM) remodeling. The ECM may play an active role in inflammation by modulating immune cell functions, including cell adhesion, but this hypothesis has not been tested in IBD.Design:Primary human intestinal myofibroblast (HIMF)-derived ECM from IBD and controls, 3D decellularized colon or ECM molecule-coated scaffolds were tested for their adhesiveness for T cells. Matrisome was analysed via proteomics. Functional integrin blockade was used to investigate the underlying mechanism. Analysis of the pediatric Crohn's disease (CD) RISK inception cohort was used to explore an altered ECM gene expression as a potential predictor for a future complicated disease course.Results:HIMF-derived ECM and 3D decellularized colonic ECM from IBD bound more T cells compared to control. Control HIMFs exposed to the pro-inflammatory cytokines Iinterleukin-1β (IL-1β) and tumor necrosis factor (TNF) increased, and to transforming growth factor-β1 (TGF-β1) decreased ECM adhesiveness to T cells. Matrisome analysis of the HIMF-derived ECM revealed collagen VI as a major culprit for differences in T cell adhesion. Collagen VI knockdown in HIMF reduced adhesion T cell as did the blockage of integrin αvβ1. Elevated gene expression of collagen VI in biopsies of pediatric CD patients was linked to risk for future stricturing disease.Conclusion:HIMF-derived ECM in IBD binds a remarkably enhanced number of T cells, which is dependent on Collagen VI and integrin αvβ1. Collagen VI expression is a risk factor for a future complicated CD course. Blocking immune cells retention may represent a novel approach to treatment in IBD.
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DOI：
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